L-aspartyl-D-alanine amides, such as disclosed in U.S. Pat. No. 4,411,925, are known to be useful as artificial sweeteners. Such amides may be synthesized by reacting a dipeptide precursor with an amine. The dipeptide precursors may be obtained using well known methods for the coupling of amino acids.
The amines required for producing the dipeptide amide sweeteners may typically be obtained via the reduction of a corresponding ketoxime using sodium/alcohol mixtures. The ketoxime may be obtained from its corresponding ketone and the ketone in turn may be prepared by reaction of the corresponding acid chloride with a Grignard reagent in ether or tetrahydrofuran at low temperature. The overall process for preparing the amine required for use in the synthesis of dipeptide amide sweeteners, therefore, may involve the use of several reaction steps, costly starting materials and the difficulty of operating with highly flammable reagents under dry, oxygen-free atmospheres. Furthermore, the low yields of some of these reaction steps may lead to low overall yields for the combined reaction steps.
In general, known processes for preparing 1-cyclopentylalkyl amines involve preparation of an alkyl cyclopentane of type (II) and then converting it to the corresponding amine. ##STR1## X=COCl, CONH.sub.2, CO.sub.2 H, OH, Br, NO.sub.2, N.sub.3, .dbd.O, .dbd.NOH, =NOCH.sub.3 (See "Compendium of Organic Synthesis Methods," Wiley-Interscience, N.Y., Vol. I (1971, ed., I. T. Harrison and S. Harrison), Vol. II (1974, ed., I. T. Harrison and S. Harrison, Vol. III (1977, ed., L. S. Hegedus and L. G. Wade), Vol. IV (1980, ed. L. G. Wade), Vol. V (1984, ed. L. G. Wade).
An example of the preparation of 1-cyclopentylethyl amine is reported in L. Bonsignore et al., CA, 89, 108266 (1978), Rend. Semin. Fac. Sci. Univ. Cagliari, (1977), 47, 1-8, wherein ethylidenecycloalkanes are hydroborated, hydrolyzed and oxidized to form the respective acetylcycloalkanes which are in turn aminated to give 1-cyclopentylethyl amine. Alternatively, cyclopentylalkyl amines may be obtained by reducing cyclopentyl methyl ketone in the presence of ammonium formate and formic acid, Smith et al., J. Amer. Chem. Soc. 76, 4564-4567, (1954).
The palladium-catalyzed reduction of bicyclic allylic ester amines to produce a cyclopentenyl glycine is described in Bourgeois-Cury et al., Tetrahedron Letters, 33, 1277-80 (1992).
Each of the above-mentioned procedures suffer from the use of multiple steps, costly starting materials, difficult reaction conditions, or low yields.